Low Creatininuria due to Hyponatremia Is Reversible in Many Patients

<b><i>Background:</i></b> Chronic hyponatremia has been reported to be associated with low solute intake and low creatinine excretion (reflecting likely sarcopenia). We wanted to study the effect, on the long term, of correction of hyponatremia on solute and creatinine excretion in chronic SIADH. <b><i>Methods:</i></b> We made a retrospective review of clinical and biochemical data of patients with euvolemic hyponatremia. We analyzed 24-h urine solute and creatinine excretion in volunteers with hyponatremia induced by dDAVP over 4 days, in 12 patients with chronic SIADH (&#x3e;1 month) before and after a few days of SNa correction and in 12 patients (6 women and 6 men) before and after 3 months of SNa correction by a vaptan or urea. <b><i>Results:</i></b> We confirm a low urine creatinine and solute excretion only in patients with chronic hyponatremia (&#x3e;1 month). Correction of SNa (from 127 ± 2.3 mEq/L to 139 ± 2.8 mEq/L) for &#x3e;3 months, in the 12 patients (mean age 58 ± 18), was associated with an increase in 24-h creatinine excretion (from 986 ± 239 to 1,238 ± 220 mg; <i>p</i> &#x3c; 0.02) and in patients treated with a vaptan (<i>n</i> = 5) solute excretion increased from 656 ± 207 mmol/24 h to 960 ± 193 mmol/24 h (<i>p</i> &#x3c; 0.02). Sodium excretion increased also in the 12 patients (from 100 ± 53 mEq/24 h to 169 ± 38 mEq/24 h; <i>p</i> &#x3c; 0.01). <b><i>Conclusion:</i></b> Chronic hyponatremia (&#x3e;1 month) is associated with a decrease in solute output (or intake) and in creatinine excretion. In many patients, these abnormalities are reversible in the long term.

Abstract P254: Sex Differences In Angiotensin Ii-induced Hypertension In Mice With Proximal Tubule-specific Deletion Of Mitochondrial Protein Sirtuin 3 In The Kidney

The development of Angiotensin II (Ang II)-induced hypertension is associated with mitochondrial dysfunction and kidney injury. Sirtuin 3 (SIRT3), a key mitochondrial protein, plays an important role in maintaining mitochondrial homeostasis. However, it remains unknown whether deletion of SIRT3 in the proximal tubules will alter the pressor and renal responses to Ang II in sex-different manners. In the present study, adult male, and female wild-type (WT) and mutant mice with proximal tubule-specific knockout of SIRT3, PT- Sirt3 -/- , were infused with or without a slow pressor dose of Ang II via an osmotic minipump (0.5 mg/kg/day, i.p.), supplemented with a 2% NaCI diet or losartan, 20 mg/kg/day, for 2 weeks. Systolic (SBP), diastolic (DBP), and mean arterial blood (MAP) pressure were determined using the tail-cuff method, whereas 24 hr. urinary sodium and potassium excretion were determined using a metabolic cage. Serum and urine creatinine were measured using colorimetric assays, whereas glomerular and tubulointerstitial injury was evaluated by Masson’s Trichrome staining. Basal SBP levels were lower in PT- Sirt3 -/- than in WT mice (SBP-WT: 112 ± 2 vs. SBP-PT- Sirt3 -/- : 93 ± 2 mmHg, P <0,01). The magnitude of Ang II-induced hypertension was similar between WT and PT- Sirt3 -/- mice with or without losartan treatment. Serum creatinine levels and urinary creatinine excretion were higher in PT- Sirt3 -/- mice than in WT mice ( P <0.05), but without significant sex differences in response to Ang II infusion or losartan treatment. Differences were found only in female WT and PT- Sirt3 -/- mice with lower 24 hr. urine and urinary creatinine excretion in response to Ang II infusion or losartan. Losartan significantly increased 24 hr. urinary potassium and chloride excretion in Ang II-infused male and female PT- Sirt3 -/- mice ( P <0.01). Finally, Ang II-infused PT- Sirt3 -/- mice showed significant renal cortical tubulointerstitial fibrotic responses ( P <0.05), but not glomerular fibrotic responses. We conclude that basal blood pressure is lower in male and female PT- Sirt3 -/- mice and that Ang II induces similar hypertensive and renal fibrotic responses in male and female PT- Sirt3 -/- mice without significant sex differences.

COMPARATIVE INFLUENCE OF TRENTHAL AND XANTHINOL NICOTINATE ON THE FUNCTIONAL STATE OF KIDNEYS IN RATS UNDER CONDITIONS OF SALT LOADING

The aim – to investigate the comparative influence of trenthal and xanthinol nicotinateon the functional state of the rat kidneys under conditions of salt loading after a singleand durable (7 days) administration of preparations.Material and methods. Changes of excretory, water- and ion-regulating functions of thekidneys following a single and long trenthal and xanthinol nicotinate administration atdoses of 3mg/kg under conditions of salt loading with NaCl solution 0,45% were studiedin the experiments on non-linear white rats.Results. Both the rapid response of the kidneys after a single injection of trenthaland xanthinol nicotinate and more significant changes of the renal function followingrepeated (7 days) drugs’ administration under conditions of salt hydration with NaCl0.45% solution were observed. Comparative estimation of the renal action at a singleadministration has shown that xanthinol nicotinate activates water-, ion-regulating andexcretory function of kidneys more significantly than trenthal. After xanthinol nicotinateadministration the urine output in rats increased 74%, natriuresis - 66%, creatinineexcretion – 52% in comparison with the control, while following trenthal administrationthe indices under study increased only 62%, 33% and 34% correspondingly.Under conditions of salt loading water-regulating function of kidneys activated moresignificantly following durable (7 days) administration than after a single introduction ofpreparations. Under trenthal influence diuresis increased 1.8 times, xanthinol nicotinate– 1.9 times in comparison with the control. Trenthal increased endogenous creatinineexcretion – 1.4 times and xanthinol nicotinate – 1.6 times.Natriuresis increased almost 2 times, trenthal - 1.4 times under xanthinol nicotinateinfluence. The natriuretic effect of xanthinol nicotinate is 55% higher than that oftrenthal. Positive correlative relation has been established between increased urinationand natriuresis only after durable xanthinol nicotinate administration (r=0,784, p<0,05).Trenthal appeared to be more pronounced kaliurretic.Conclusions. Excretory, water- and ion-regulating renal function is activated following asingle and protracted (7 days) introduction of methylxanthine derivatives – trenthal andxanthinol nicotinate at a dose of 3mg/kg under hydration conditions with NaCl solution0,45%. Renal effects of the preparations under study is characterized by an increaseof endogenous creatinine excretion. With long-term administration of the preparationsnatriuretic effect predominates in xanthinol nicotinate, kaliuretic effect - in trenthal.

Protective Role of Fisetin in STZ Induced Diabetic Nephropathy in Rats

Objectives: Chronic diabetes mellitus associated with devastating complication the diabetic nephropathy, that further progress to ESRD,a major cause of morbidity and premature mortality in many countries worldwide. Accumulated evidences demonstrated that long standing hyperglycemia induced oxidative stress, inflammatory cytokines, and fibrosis plays a significant role in DN. Fisetin, a bioflavonoid, exhibited variety of promising pharmacological properties such as, anti-diabetic, antioxidant, anti-inflammatory, anti-hyperlipidemic ,and anti-carcinogenics. Hence, the present study was hypothesized to investigate, the effect of fisetin on streptozotocin-induced diabetic nephropathy in rats. Materials and Methods: Sprague Dawley rats were divided into 6 groups (n=6) as normal control, diabetic control (vehicle), Glimepiride (0.5 mg/kg, orally) and Fisetin treatment (2.5, 5 and 10 mg/kg, orally) groups. After the confirmation of diabetes, vehicle/drug treatments were started and continued for 6 weeks. Serum glucose, body weight, were measured on weekly basis.Thereafter, on the last day of treatment protocol, ie 42 day, serum insulin, HbA1c in blood, lipid parameters, creatinine, albumin and urea in serum and in urine creatinine excretion, albumin were measured along with urine volume and creatinine clearance. In addition, weight of kidney and histopathological studies were carried out. Results: Fisetin treatment significantly attenuated reduction in body weight. Also, it significantly decreased the blood glucose level, ameliorate lipid profile and HbA1c (p<0.05) value, but serum insulin level were not much influenced. It also increased albumin in serum, decreased serum urea and creatinine and in urine, it reduced the urine volume, albumin with marked improvement in creatinine excretion and creatinine clearance. Further, the fisetin (10mg/kg) treatment attenuated oxidative stress and cytokines TNF-α (p<0.01), IL-1β (p<0.01), and IL-6 (p<0.05) level in kidney tissue along with amelioration of histopathological alterations compared to diabetic control rats. The standard drug, glimepiride also exhibited similar antidiabetic effect without much influence on oxidative stress, albumin in urine, and cytokine levels. Conclusions: The results indicated that fisetin ameliorated diabetic nephropathy through its antidiabetic and antioxidant effect which may be attributed to inhibition of downward pathway of glycemia induced oxidative stress, inflammation and necroptosis of renal tissue.

Development of the proteinuria dosage

The 24-hour urine proteinuria or albuminuria ratio is still prescribed for protein detection in urine, despite the fact that it has been replaced by the albuminuria or protein/creatininuria ratio. The use of this ratio eliminates the misinterpretation of 24-hour urine proteinuria. The objective of this development is to clarify the importance of the ratio for the search for albumin or protein in the urine. We conducted a review of the literature focusing on different diagnostic recommendations. Indeed, 24-hour urine collection is tedious and prone to many errors. The ratio is therefore a simple, reliable and standardized indicator for assessing proteinuria except in acute renal failure patients. The correlation between these ratios and 24-hour urine has been demonstrated in several studies in various populations and is currently considered to be the most adequate measure for proteinuria quantification despite the variability in creatinine excretion. The Kidney Disease Improving Global Outcomes recommendations therefore suggest the use of the albumin/creatinine ratio and the protein/creatinine ratio on a 1st morning urine sample to test for proteinuria.

Variability of Urinary Creatinine in Healthy Individuals

Many urinary biomarkers are adjusted for dilution using creatinine or specific gravity. The aim was to evaluate the variability of creatinine excretion, in 24 h and spot samples, and to describe an openly available variability biobank. Urine and blood samples were collected from 60 healthy non-smoking adults, 29 men and 31 women. All urine was collected at six time points during two 24 h periods. Blood samples were also collected twice and stored frozen. Analyses of creatinine in urine was performed in fresh urine using an enzymatic method. For creatinine in urine, the intra-class correlation (ICC) was calculated for 24 h urine and spot samples. Diurnal variability was examined, as well as association with urinary flow rate. The creatinine excretion rate was lowest in overnight samples and relatively constant in the other five samples. The creatinine excretion rate in each individual was positively correlated with urinary flow rate. The creatinine concentration was highest in the overnight sample and at 09:30. For 24 h samples the ICC was 0.64, for overnight samples it was 0.5, and for all spot samples, it was much lower. The ICC for urinary creatinine depends on the time of day of sampling. Frozen samples from this variability biobank are open for researchers examining normal variability of their favorite biomarker(s).

FURTHER STUDIES ON URINARY 3-METHYLHISTIDINE EXCRETION AS AN INDIRECT INDEX OF DIETARY AMINO ACID ADEQUACY IN RATS

As a further step in the determination of the sen­sitivity of urinary 3-methylhistidine (3-MeH) to essential amino acid adequacy in diet, 36 male albino rats of the Wistar strain were divided into six groups +of six rats per group. Each group with an initial .mean live weight of 106.52 ± 0.54g was fed in in­dividual metabolic cages on a basal diet sup­plemented with graded levels of DL-methionine. Total methionine in diet ranged between 0.25 and 1.05%. The study lasted 10 days. The response of urinary 3-methylhistidine excretion to the graded levels of methionine in diet was compared to responses obtained from growth performance characteristics, plasma urea concentration, liver nitrogen and creatinine excretion. With the excep­tion of feed intake, all other indices of dietary pro­tein adequcy and efficient amino acid utilization viz growth rate, protein efficiency ratio, serum urea concentration, and creatinine excretion were significantly (P 0.05) to P 0.01) influenced by dietary methionine level. Maximum growth rate, liver N and urinary 3-methylhistidine were observed. in rats given 0.45% total methionine in diet. Supplementing the basal diet to contain 0.45% total,' methonine significantly (P 0.01) decreased serum urea concentration. Urinary 3-methylhistidlne excre­tion was found by regression analysis to be positively correlated to body weight gain (r = 0.73), feed intake (r = 0.61), urinary creatinine excretion (r = 0.74) and liver N (0.72) but negatively correlated to dietary methionine level (r = —0.41). We suggested that urinary 3-MeH excretion be added to the list of available indicts for dietary amino acid adequacy.